Term
| portal htn is defined as a portal pressure greater than? |
|
Definition
|
|
Term
| portal htn in cirrhosis arises from a blockade of which vessels? |
|
Definition
| intra-hepatic vessels (sinusoidal and post-sinusoidal d/t contraction of vascular smooth muscle cells and disruption of blood flow by scarring and formation of nodules) |
|
|
Term
| what in the liver is responsible for producing NO? |
|
Definition
|
|
Term
| portal htn is d/t 3 main components: |
|
Definition
| 1. structural changes in the sinusoidal cells (capillarization - disappearance of fenestrae) 2. actual blocks within the liver, cirrhotic nodules (collagen deposition in the space of disse, fibrosis) 3. decrease in NO production by sinusoidal endothelial cells and increased sensitivity to vasoconstrictors |
|
|
Term
| 3 features characterize cirrhosis systemically, they are: |
|
Definition
| 1. hyperdynamic circulation 2. systemic vasodilation 3. sodium avidity |
|
|
Term
| systemic vasodilation in the cirrhotic state are sensed by what structures? what is their response to this vasodilation? |
|
Definition
| carotid and aortic baroreceptors and volume receptors in atrium --> stimulation of noradrenaline secretion |
|
|
Term
| desribe what happens to free water clearance in cirrhosis |
|
Definition
| altered, we retain more water when we're cirrhotic (although not in the arterial bed bc of vasodilation, therefore kidneys are not well perfused) |
|
|
Term
| what happens to plasma vol and cardiac output in patients with cirrhosis? peripheral resistance? what causes these effects |
|
Definition
| both increased and peripheral resistance decreased. caused by increased activity of plasma renin and aldosterone |
|
|
Term
| describe changing NO levels in the liver and systemically in cirrhosis |
|
Definition
| intrahepatic decrease in NO production by sinusoidal endothelial cells; systemically EXCESS NO production, which mediates the peripheral vasodilation |
|
|
Term
| what is the most important determining factor in the prognosis if cirrhosis? |
|
Definition
| ascites development (accumulation of lymph in abdominal cavity) |
|
|
Term
| ascites can be d/t a # of causes. what lab value will point to portal htn as the etiology of ascites? |
|
Definition
| serum plasma to ascites albumin gradient > 1.1 g/dL |
|
|
Term
| describe the 2 types of hepatorenal syndrome |
|
Definition
| HRS1 progressive impairment of renal function defined as doubling of baseline serum creatinine above 2.5 mg/dL in less than 2 weeks. HRS2 stable or slowly progressive impairment of renal function not meeting HRS1 criteria |
|
|
Term
| what are a few ways we treat ascites |
|
Definition
| bed rest with diet of Na restriction <2g/day; diuretics; paracentesis (give album or risk renal insufficiency!); transjugular intrahepatic portal-systemic shunt (risk mental status change); liver transplant |
|
|
Term
|
Definition
| beta blockers to decrease splanchnic circulation and portal htn; tx with banding of varices |
|
|
Term
| what are some things that cause infections in cirrhotic patients |
|
Definition
| impaired reticuloendothelial system (d/t splenomegaly); portosystemic shunting (get toxic stuff in systemic circulation --> hypergammaglobulinemia); increased intestinal permeability; contamination of ascites fluid (seeding from LN) |
|
|
Term
| what is probably responsible for the increase in circulating ammonia associated with encephalopathy in cirrhosis |
|
Definition
| portosystemic shunting --> bacteria create ammonia in gut --> systemic circulation --> brain |
|
|
Term
| how does gabaergic neurotransmission mediate encephalopathy in cirrhotic patients |
|
Definition
| increased availability of endogenous benzodiazepines --> conformation change of gaba receptor --> cl- comes into the cell --> inhibitory neurotransmission |
|
|
Term
| injury of which cell in the liver stimulates the fibrotic process? |
|
Definition
| ito cells (stellate cells) --> injury induces them to become facultative fibroblastic cells --> deposit collagen in the liver (space of disse - normally has thin strands of type IV collagen while rest of liver has type I and III. in pathology, collagen types I and III are deposited in space of disse) --> cirrhosis |
|
|
Term
| the preservation of _______ in the liver permits complete regeneration (reversible injury) following insult, whereas their destruction leads to scarring, fibrosis, and irreversible cirrhosis. |
|
Definition
| reticulin (stacks of collagin in space of disse produced by ito cells) |
|
|
Term
| fulminant liver failure is what? |
|
Definition
| when encephalopathy develops within 2 weeks of onset of jaundice |
|
|
Term
| what are the main causes of fulminant liver failure? |
|
Definition
| acetomenaphen OD (50%); autoimmune (15%); exposure to toxins (15%); HBV (8%); HAV (4%) |
|
|
Term
| main causes of hepatorenal syndrome? |
|
Definition
| sodium retention, impaired free-water excretion, decreased renal perfusion, decreased glomerular filtration rate |
|
|
Term
| hepatopulmonary syndrome diagnosed by classic triad |
|
Definition
| chronic liver disease, hypoxemia, intrapulmonary vascular dilations |
|
|
Term
| what is the key mediator in hepatopulmonary syndrome? |
|
Definition
| enhanced production of NO by the lung (causes rapid blood flow thru pulmonary vessels --> lack of uniform blood flow, ventilation perfusion mismatch, limitation of oxygen diffusion...) |
|
|
Term
| nodularity in the liver is a result of what pathologic process? |
|
Definition
| cycles of hepatocyte regeneration and scarring, confined by fibrous septa |
|
|
Term
| what causes the arterial vasodilation (increase in NO) in cirrhosis? |
|
Definition
| portosystemic shunt --> blood bypasses the kupffer cells --> decreased function of kupffer cells (macrophage/phagocytosing function) --> reduced clearance of bacterial DNA absorbed from the gut --> NO production stimulated |
|
|
Term
| what creates "feathery degeneration" |
|
Definition
| cholestasis --> accumulation of droplets of bile pigment in the hepatocytes --> fine foamy appearance of hepatocytes |
|
|
Term
| diffuse parenchymal damage (pan-acinar) is characteristic of which 3 types of liver damage? |
|
Definition
| fulminant hepatic injury, fulminant acute viral hepatitis, severe hepatotoxic drug reaction |
|
|
Term
| periportal damage denotes what kind of liver pathology? |
|
Definition
| piecemeal necrosis --> chronic viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis |
|
|
Term
| pericentral damage is indicative of what liver pathology? |
|
Definition
| chemical toxicity, ischemia |
|
|
Term
| what are the four characteristic histological findings associated with alcoholic hepatitis? |
|
Definition
| 1. hepatocyte swelling and necrosis; 2. mallory bodies (cytokeratin 8 and 18) 3. neutrophilic rxn (accumulate in area of degeneration) 4. fibrosis (almost always activation of ito cells --> fibrosis) |
|
|
Term
| 3 causes of fatty liver change |
|
Definition
| 1. excess NADH from alcohol metabolism 2. impaired assembly and secretion of lipoproteins 3. increased peripheral catabolism of fat |
|
|
Term
| 3 primary pathways of alcohol degradation |
|
Definition
| 1. cytosolic alcohol dehydrogenase (>80%) 2. microsomal ethanol oxidizing system 3. catalase |
|
|
Term
| alcohol dehydrogenase acts in what part of the liver? |
|
Definition
| hepatocellular cytosol (activity genetically determined) |
|
|
Term
| what is the primary enzyme of the microsomal ethanol oxidizing system? where does it work? |
|
Definition
| cytochrome P4502E1; inducible by several drugs and alcohol consumption; works in microsome (ER) |
|
|
Term
| where does catalase work? |
|
Definition
| peroxisome, mitochondria, role is minimal |
|
|
Term
| what are the consequences of having high NADH |
|
Definition
| increased a-glycerophosphate levels --> increased FA synthesis and hepatocellular accumulation of trigs; decreased mitochondrial oxidation of FA --> further intrahepatocyte accumulation of FA |
|
|
Term
| what is the consequence of having high acetylaldehyde? |
|
Definition
| microtubular alterations --> disrupt protein secretion and water/electrolyte transport --> ballooning degeneration (hepatomegaly and cellular necrosis); also binds glutathione and depletes concentration of free radical scavengers --> increases lipid peroxidation and decreases ability to scavenge drug metabolites |
|
|
Term
| what are the clinical findings of fatty liver? |
|
Definition
| hepatomegaly, normal LFTs, minimal ALP increase, centrilobular steatosis on bx |
|
|
Term
| what are the clinical manifestations of alcoholic hepatitis? |
|
Definition
| anorexia, weight loss, fever, fatigue, RUQ pain, nausea; hepatomegaly, jaundice, ascites, peripheral edema, encephalopathy; increased LFTS (<300 IU/L usually), elevated ALP; bx: hepatocellular necrosis, pmn infiltration, pericentral fibrosis, mallory bodies |
|
|
Term
| what are the 3 ways drugs/toxins can induce liver injury? |
|
Definition
| 1. direct toxicity of hepatocytes of biliary epithelial cells --> necrosis, apoptosis, disruption of cellular function (production of free radicals) 2. hepatic conversion of xenobiotic to an active toxin (electrophilic metabolite of offending drug produced by p450 system, escapes detoxification and covalently binds to cellular constituents disturbing their function) 3. immune mechanisms (drug or metabolite acting as a hapten to convert cellular protein to immunogen; prototype is halothane) |
|
|
Term
| describe how halothane leads to liver injury |
|
Definition
| prototypic immunologic mediated injury; metabolite (trifluoroacetyl) reacts with hepatocellular proteins --> patient develops serum antibodies to these neoantigens |
|
|
Term
| budd-chiari syndrome associated with? |
|
Definition
|
|
Term
|
Definition
| rare and potentially fatal syndrome of mitochondrial dysfunction (pleomorphic enlargement, disruption of ultrastructure, distortion of cristae, formation of electron-lucent matrices) in liver, brain, elsewhere; children; extensive accumulation of fat droplets (microvesicular steatosis); assoc with aspiriin use for relief of fever; progressive hepatic failure and encephalopathy |
|
|
Term
|
Definition
| hemorrhage and circulatory collapse --> DIC --> necrosis of hepatic parenchyma; characterized by maternal HTN, proteinuria, peripheral edema, coag abn; hyper-reflexia and convulsions |
|
|
Term
| who is susceptible to acute fatty liver of pregnancy? and what causes it? |
|
Definition
| women in 3rd trimester of pregnancy; when both mother and father carry heterozygous deficiency in mitochondrial long-chain 3-hydroxyacyl coenzyme A dehydrogenase. homozygous deficient fetus --> 3-hydroxylacyl metabolites produced by fetus or placenta washed away into maternal circ --> hepatic toxicity |
|
|
Term
| what are the clinical findings of acute fatty liver of pregnancy? |
|
Definition
| microvesicular steatosis on bx; bleeding, nausea, vomiting, jaundice, coma; most commonly runs a mild course but can progress within days to hepatic failure and death |
|
|
Term
| what is the primary tx for acute fatty liver of pregnancy? |
|
Definition
|
|
Term
| what causes intrahepatic cholestatis of pregnancy? |
|
Definition
| altered hormonal state of pregnancy + biliary defects --> pure benign cholestasis (steroid-induced hepatocellular damage). |
|
|
Term
| what are the clinical findings of intrahepatic cholestasis of pregnancy? |
|
Definition
| pruritis in 3rd trimester (can be really bad); darkening of urine, light stools, jaundice; puts mother at risk for gallstones and malabsorption; increased incidence of fetal distress, still births and premature birth |
|
|
Term
| tx for intrahepatic cholestasis of pregnancy? |
|
Definition
|
|
Term
| what is the common cause of liver abscesses in developing countries? |
|
Definition
| parasitic infections, protozoa, helminths |
|
|
Term
| what is the common cause of liver abscesses in non-developing countries? |
|
Definition
| bacterial origin, complication of infection elsewhere |
|
|
Term
| describe the pathogenesis of autoimmune hepatitis and what it's genetically associated with |
|
Definition
| T-cell mediated autoimmunity in which hepatocyte injury is caused by IFN-gamma produced by CD4 and CD8 cells and by CD8 T-cell mediated cytotoxicity; genetic factors play a role (HLA-B1, B8, DR3, and DR4, DRB1) are common and also common are associations with other autoimmune disorders (sjogrens, lupus, RA, UC) |
|
|
Term
| Type I autoimmune hepatitis associated with what pattern of circulating autoantibodies? and which HLA haplotypes |
|
Definition
| (young women) anti-nuclear antibodies, anti-actin antibodies, anti-smooth muscle antibodies, pANCA, and HLA-DR3, DR4 |
|
|
Term
| autoimmune hepatitis Type II associated with what pattern of autoantibodies? and which HLA haplotypes |
|
Definition
| (children, mediterranean) anti-liver kidney microsome-1 (ALKM-1) antibodies, anti-liver cytosol-1 (ACL-1), HLA-DRB1, HLA-DQB1 |
|
|
Term
| what is histologically characteristic of autoimmune hepatitis? |
|
Definition
| clusters of plasma cells in the interface of portal tracts and hepatic lobules |
|
|
Term
| low-flow states (as with shock or left ventricular failure) results in ischemia of which zone of hepatic acinus? |
|
Definition
|
|
Term
| what are 2 things that might cause sinusoidal occlusion and therefore hepatic infarction? |
|
Definition
|
|
Term
| acute impairment of vascular outflow in the liver will result in what kind of damage to the liver? |
|
Definition
| centrilobular congestion, hemorrhagic necrosis |
|
|
Term
| chronic impairment of vascular outflow in the liver will result in what sort of damage? |
|
Definition
| atrophy of centrilobular hepatocytes, pericentral fibrosis |
|
|
Term
| what causes the characteristic nutmeg liver? |
|
Definition
| combination of right sided heart failure --> passive liver congestion; + left sided heart failure --> hepatic hypoperfusion and necrosis in zone3 (centrilobular necrosis); together = centrilobular hemmorhagic necrosis --> variegated, mottled red apperance = NUTMEG LIvER! |
|
|
Term
| what is budd-chiari syndrome? |
|
Definition
| obstruction of two or more major hepatic veins --> liver enlargement, pain, ascites (massive passive congestion), dilation of central veins and sinusoids, fibrosis |
|
|
Term
| what are some of the more common causes behind hepatic veno-occlusive disease? |
|
Definition
| hepatotoxic alkaloids found in jamaican bush tea; post-allogenic-bone-marrow-transplant; anti-neoplastics, immunosuppressants, hepatic irradiation. |
|
|
Term
| describe the pathogenesis of veno-occlusive disease |
|
Definition
| toxic injury to sinusoidal endothelium --> endothelial lining cells round up and slough off the sinusoidal wall --> embolize downstream and obstruct sinusoidal blood flow --> accumulation of cellular debris in central vein; also, proliferation of ito cells and subendothelial fibroblasts in central vein --> fibrosis and deposition of ECM in the sinusoids -->obliteration of the small veins of the liver (thrombosis may propagate to larger hepatic veins mimicking budd-chiari) |
|
|
Term
| annular pancreas is associated with what other condition? |
|
Definition
|
|
Term
| what is a macroamylase and what lab findings will pick it up? |
|
Definition
| heterogenous complex of normal amylase + IgA, IgG or polysaccharide. persistant increase in serum amylase with normal or low urine amylase |
|
|
Term
| what is the etiology of cystic fibrosis? |
|
Definition
| autosomal recessive disorder of ion transport. mutation of transmembrane conductance regulator (CFTR) gene on chromosome 7 --> encodes epithelial chloride channel protein --> defective chloride transport --> abnormally dehydrated tenacious secretions of all exocrine glands. heterozygotes no clinical sx. |
|
|
Term
| what are the clinical signs of cystic fibrosis |
|
Definition
| recurrent pulm inf, pancreatic insufficiency (thick secretions plug ducts, cause chronic inflammation with atrophy of acini, fibrosis, dilatation, cystic duct changes --> pancreatic lipase deficiency --> malapsorption of fat & nutrients --> steatorrhea & malnutrition) men infertile d/t duct obstruction (azospermia), sweat chloride level elevated (>60mmol/L diagnostic) |
|
|
Term
| how do we dx hemochromatosis? |
|
Definition
| transferrin saturation >60% in men and >50% in women --> confirm with fasting transferrin saturation and ferritin levels --> liver bx with assay for iron to confirm and assess extent |
|
|
Term
| what effect does hemochromatosis have on the pancreas? other organs? (pathophysiology) |
|
Definition
| iron deposits in acinar cells, duct cells, B cells of the islets --> pancreas slightly enlarged, deep brown d/t accumulated hemosiderin --> progressive fibrosis with atrophy --> "bronze" diabetes d/t similar pigmentation in skin (hemosiderin + increase in melanin prod). hypogonadism (atrophy, infertility), pituitary dysfunc, cardiomegaly, psuedo-gout, cirrhosis, hcc) |
|
|
Term
| what are the 3 main features characterizing hemochromatosis? |
|
Definition
| micronodular cirrhosis, diabetes mellitus, skin pigmentation |
|
|
Term
| hereditary hemochromatosis etiology |
|
Definition
| HLA-linked, autosomal recessive, d/t mutation in HFE (located on short arm of chromosome 6) --> lack of hepcidin expression --> iron overload |
|
|
Term
| what is the name for pancreatic changes associated with protein-calorie malnutrition? |
|
Definition
|
|
Term
| what are the causes of idiopathic acute pancreatitis? |
|
Definition
| (10-20%) germline mutations of PRSS1 (cationic trypsinogen gene) --> alteration of a site that is essential for the inactivation of trypsin by trypsin itself --> trypsin becomes resistant to cleavage by other trypsin molecules --> trypsin activated in pancreas --> can activate other digestive enzymes --> pancreatitis!; germline mutation of SPINK1 (pancreatic secretory trypsin inhibitor) --> pancreas not protected against autodigestion by activated trypsin --> pancreatitis |
|
|
Term
| what accounts for 80% of the cases of acute pancreatitis in western world? |
|
Definition
| alcoholism and biliary tract disease (gallstones also frequently found) |
|
|
Term
| what are the 2 subtypes of acute pancreatitis that we can histologically identify? |
|
Definition
| 1. incidental/edematous pancreatitis (mild) 75-80% - peripancreatic fat necrosis (from enzymatic activity of lipase) and interstitial edema, no mortality, spontaneous recovery. 2. hemorrhagic pancreatitis (severe) necrosis of pancreas with hemorrhage may cause shock and death, necrosis starts coagulative then liquefactive |
|
|
Term
| what is the basic pathophysiology behind acute pancreatitis? |
|
Definition
| premature activation of inactive proenzyme trypsinogen to trypsin --> activates most of theo ther digestive enzymes --> tissue damage and necrosis of pancreas, surrounding fat and adjacent struc |
|
|
Term
| what are 3 possible complications of acute pancreatitis? |
|
Definition
| hypocalacemia, mild jaundice, sepsis-like syndrome d/t digestive enzymes in the systemic circ --> systemic immune response syndrome w/severe systemic complications (75% of patients with acute pancreatitis recover) |
|
|
Term
| what lab tests do we do to check for acute pancreatitis? |
|
Definition
| serum amylase (rises 2-12 hrs after onset, peak 20-30 hrs, wnl in 3-5 days); urinary amylase (rises 6-10 hrs after onset, persists for 4 days); amylase can be nonspecific, so do serum lipase to confirm pancreatic etiology (increases in 4-8 hrs, elevated for 8-14 days); hyperglycemia, elevated bilirubin, leukocytosis; negative serum trypsinogen-2 level excludes acute pancreatitis |
|
|
Term
| what is the cause of idiopathic chronic pancreatitis? |
|
Definition
| d/t cystic fibrosis, caused by mutation of CFTR gene --> protein plugging of ducts --> other features of cystic fibrosis absent |
|
|
Term
| describe mucinous cystadenomas |
|
Definition
| women, multiloculated, lined by mucin-producing columnar epithelium, may be malignant |
|
|
Term
| describe serous cystadenomas |
|
Definition
| 7th decade of life, benign, produce a palpable mass, variably sized cysts lined by cuboidal epithelial cells with clear, glycogen-rich cytoplasm |
|
|
Term
| what are some risk factors for pancreatic carcinoma? |
|
Definition
| old age, male predominance, blacks, native americans, cig smokers, chronic pancreatitis, diabetes mellitus, alcohol, coffee |
|
|
Term
| what is courvoisier sign? |
|
Definition
| acute painless dilatation of the gallbladder d/t common bile duct obstruction by tumor (1/3 of pancreatic carcinoma pts) |
|
|
Term
|
Definition
| migratory thrombophlebitis, paraneoplastic feature of pancreatic carcinoma (10%) --> d/t platelet aggregating factors and procoagulants from the tumor |
|
|
Term
| describe intraductal papillary mucinous neoplasm |
|
Definition
| arise in main duct or major branches, produce benign and malig cysts that contain mucin, classified according to degree of epithelial atypia |
|
|
Term
|
Definition
| pancreatic carcinoma that arises in the common bile duct --> localized resection can remove it |
|
|
Term
| what is the most frequently altered oncogene in pancreatic cancer? |
|
Definition
|
|
Term
| what is the most frequently inactivated tumor suppressor gene in pancreatic cancer? (next?) |
|
Definition
|
|
Term
| what are KRAS, CEA and CA19-9 useful for in pancreatic cancer? |
|
Definition
| if theyre elevated upon diagnosis, can be used to monitor recurrence |
|
|
Term
| why are some gastrinoma patients hypercalcemic? |
|
Definition
| parathyroid-hormone production or bc patients with MEN1 (1/3 of the time assoc with ZES) may develop hyperparathyroidism |
|
|
Term
| what % of ZES patients have malignant tumors? what % have metastases?: |
|
Definition
| 70-90% malignant at diagnosis; 50% metatstatic, mostly to liver |
|
|
Term
|
Definition
| rare, origin is alpha cells of pancreas --> secrete glucagon --> glycogenolysis (breakdown of glycogen) and gluconeogenesis (generation of glucose) --> raise blood glucose levels --> mild diabetes, necrotizing migratory erythematous rash, anemia, venous thromboses, severe infections; 40-70 yrs, female predominance, 2/3 malignant, large tumors, locally invasive |
|
|
Term
|
Definition
| delta cells; rare, solitary; inhibits pituitary release of growth hormone and inhibits secretion by alpha, beta, D cells, regulates glucose homeostasis.--> mild diabetes, gallstones, steatorrhea, hypochlorhydria (d/t inhibitory effect of somatostatin on other islet and neuroendocrine cells) may also secrete ACTH and calcitonin; most malig with mets at dx |
|
|
Term
|
Definition
| rare; induces glycogenolysis and hyperglycemia --> explosive and profuse watery diarrhea with hypokalemia and hypochlorhydria. large, solitary, malig |
|
|
Term
|
Definition
| in islets in head of pancreas --> stimulates gastric mucosal enzyme secretion that inhibits production of gastric acid and exocrine pancreas secretions and exocrine pancreas secretions; tumors single; benign; no clinical syndrome |
|
|
Term
|
Definition
| synthesize seratonin and motilin. rare, malig. atypical carcinoid syndrome: facial flush, hypotension, periorbital edema, lacrimation; (liver mets = classical carcinoid syndrome) |
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